American Journal of HematologyMultiple Myeloma: 2026 Update on Diagnosis, Risk-Stratification and Management

✅ Guideline Update

This American Journal of Hematology update summarizes current recommendations for the diagnosis, risk stratification, and treatment of multiple myeloma. The review incorporates recent randomized trial data supporting anti-CD38-based quadruplet induction regimens, updated definitions of high-risk disease, evolving maintenance approaches, and expanding roles for CAR-T cell therapy, bispecific antibodies, and belantamab mafodotin in relapsed disease. The article serves as an expert synthesis of contemporary myeloma management rather than new primary research, providing a practical snapshot of current treatment paradigms and areas of ongoing debate.

Clinical Considerations

• Multiple myeloma diagnosis requires ≥10% clonal plasma cells or plasmacytoma plus CRAB features or established myeloma-defining biomarkers.
• High-risk disease now includes del(17p), TP53 mutation, bi-allelic del(1p), or specific combinations involving gain(1q), del(1p), t(4;14), t(14;16), or t(14;20).
• Preferred frontline therapy for eligible patients is anti-CD38 antibody plus VRd quadruplet therapy (Dara-VRd or Isa-VRd) followed by consideration of autologous stem cell transplantation.
• Contemporary maintenance therapy favors lenalidomide plus daratumumab or isatuximab, with risk-adjusted duration strategies.
• Relapsed disease management increasingly incorporates CAR-T cell therapy, BCMA-directed bispecific antibodies, teclistamab-based regimens, talquetamab, and belantamab mafodotin.
• Daratumumab administered for three years is recommended for patients with high-risk smoldering multiple myeloma based on recent survival and progression data.

Practice Applications

• Recognize updated cytogenetic definitions of high-risk disease when selecting induction, transplant, and maintenance strategies.
• Review whether anti-CD38-based quadruplet regimens are appropriate frontline options for newly diagnosed patients.
• Evaluate CAR-T cell therapy and bispecific antibodies earlier in relapse management discussions given growing evidence supporting these approaches.
• Discuss risk-adapted maintenance duration and MRD-guided treatment questions with patients while recognizing that some de-escalation strategies remain under investigation.
• Monitor emerging evidence regarding immunotherapy sequencing, MRD-directed treatment modification, and evolving approaches to high-risk smoldering myeloma.